The Hedgehog signaling pathway composed of the human genes Sonic Hedgehog (Shh) and Indian Hedgehog, collectively referred to herein as Hedgehog, as well as Patched (Ptc), Smoothened (Smo), Suppressor Of Fused [Su(Fu)] and Gli1, has been implicated in the pathogenesis of certain cancers (Bale & Yu (2001) Hum. Mol. Genet. 10:757-62; Pasca di Magliano & Hebrok (2003) Nat. Rev. Cancer 3:903-11; Ruiz i Altaba (1999) Trends Genet. 15:418-25; Taipale & Beachy (2001) Nature 411:349-54; Murone, et al. (1999) Exp. Cell Res. 253:25-33), consistent with its substantial role in regulating both cellular proliferation and cell fate determination during development (Ogden, et al. (2004) Biochem. Pharmacol. 67:805-14).
Hedgehog signaling is engaged when Hedgehog binds to its receptor Ptc. In the absence of Hedgehog, Ptc is required to keep the Hedgehog pathway in an off state. Thus, Hedgehog binding relieves the negative action of its receptor (Ogden, et al. (2004) supra). Ptc expression is induced in response to Hedgehog, and increased Ptc tethers Hedgehog to responsive cells, limiting the distribution of the ligand via a negative-feedback mechanism. Ptc normally inhibits the seven transmembrane domain protein, Smo, which is required for all aspects of Hedgehog signaling (Ogden, et al. (2004) supra). Smo has some identity to the guanine nucleotide binding protein coupled receptor superfamily, and is classified as a member of the Frizzled family. Smo activates the Hedgehog pathway by affecting the activity of members of the Gli family of transcription factors, Gli1-3. Gli2 and Gli3 are most related, based on primary sequence and function, and mice lacking Gli2 or Gli3 have severe developmental abnormalities. The precise role of Gli1 in Hedgehog signaling is unknown, as mice lacking Gli1 exhibit no obvious phenotype. Thus, it has been proposed that Gli1 may not be a direct regulator of the Hedgehog pathway, as Gli2 and Gli3 appear to be, but is involved in a feedback or maintenance program, which allows Hedgehog signaling in a Hedgehog-independent fashion. This suggestion is consistent with the observation that Gli1 is a Hedgehog target gene (Lee, et al. (1997) Development 124:2537-52) and with the role Gli1 plays in human oncogenesis, in which tumor cell proliferation is blocked when Gli1 levels are reduced (Ruiz i Altaba (1999) supra; Sanchez, et al. (2004) Proc. Natl. Acad. Sci. USA 101:12561-6; Dahmane, et al. (1997) Nature 389:875-81; Grachtchouk, et al. (2000) Nat. Genet. 24:216-7).
Individuals suffering from the rare inherited developmental disorder known as Gorlin's syndrome (Hahn, et al. (1996) Cell 85:841-51; Hahn, et al. (1996) J. Biol. Chem. 271:12125-8; Johnson, et al. (1996) Science 272:1668-71) not only have developmental defects, but also have an inherited predisposition to basal cell carcinoma (BCC), rhabdomyosarcoma and medulloblastoma. Mutations in this inherited disorder map to the Ptc gene, which encodes the Hedgehog receptor. The loss-of-function mutations found in both hereditary and sporadic cases of BCC implicate Ptc as a tumor suppressor in this common human cancer (Bale & Yu (2001) supra; Quinn & Epstein (2003) Methods Mol. Biol. 222:85-95). Consistent with the critical role of Ptc as a tumor suppressor, mice heterozygous for Ptc develop a similar spectrum of cancers as Gorlin's syndrome patients (Goodrich, et al. (1997) Science 277:1109-13). Other components of the Hedgehog pathway, such as the gene encoding Smo, are also often mutated in sporadic forms of these same malignancies, further suggesting a role of the Hedgehog signaling pathway in certain human cancer (Xie, et al. (1998) Nature 391:90-2).
Constitutive activation of the Hedgehog pathway has been detected in non-small cell lung carcinoma tissue (NSCLC; Watkins & Peacock (2004) Biochem. Pharmacol. 68:1055-60) and implicated as a required event in other human cancers, including breast cancer, prostate cancer, pancreatic cancer and small cell lung carcinoma (SCLC) (Lewis (2001) J. Mammary Gland Biol. Neoplasia 6:53-66; Vorechovsky, et al. (1999) Eur. J. Cancer 35:711-3; Kubo, et al. (2004) Cancer Res. 64:6071-4; Berman, et al. (2003) Nature 425:846-51; Watkins & Peacock (2004) supra; Fan, et al. (2004) Endocrinology 145:3961-70; Karhadkar, et al. (2004) Nature 431:707-12; Sanchez, et al. (2004) supra; Sheng, et al. (2004) Mol. Cancer. 3:29). In the tumors examined, no mutations of Ptc or Smo were found. Instead, increased production of Hedgehog, in an autocrine fashion, was implicated in tumor maintenance. In these tumor cells, Hedgehog is required as a mitogen (Watkins, et al. (2003) Nature 422:313-7; Karhadkar, et al. (2004) supra; Sanchez, et al. (2004) supra; Berman, et al. (2002) Science 297:1559-61). Additionally, hyper-activation of Hedgehog signaling has been found to act as a reliable marker of clinically aggressive human tumors (Karhadkar, et al. (2004) supra). Many cell lines of these tumors appear to require Hedgehog signaling for their survival, as the addition of Hedgehog pathway antagonists confers tumor cell apoptosis. Similar results were obtained when mice carrying xenografts of various human tumors were treated with Hedgehog pathway antagonists (Berman, et al. (2003) supra; Karhadkar, et al. (2004) supra). Furthermore, after the tumor regressed it did not reappear after completion of the treatment.